Understanding the tick-rickettsia interaction in nature is a logical focus to attack for the control of spotted fever group rickettsioses. This grant application proposes to investigate the hypothesis that the pathogenicity of spotted fever group rickettsiae is a limiting factor for the dispersal of these organisms in nature because of the deleterious effects of the rickettsiae on the ticks. The parent grant which is also focused on spotted fever group rickettsiae is engaged in the analysis of the structural and molecular composition of these organisms and their stimulation of immunity. Because spotted fever group rickettsiae have evolved in ticks which lack immunity, the rickettsial surface proteins are likely to have undergone natural selection for reasons related to their interactions with ticks rather than with mammalian immune systems. Thus, this project proposes to compare the effects of infections of two species of natural host ticks with pathogenic and nonpathogenic strains of Rickettsia sibirica on the viability and number of offspring of the ticks. In areas where there are no human cases but a high proportion of infected ticks and areas where there are many human cases but only a low proportion of infected ticks, ticks will be examined to determine whether they contain the pathogenic or nonpathogenic type of Rickettsia sibirica. It is our hypothesis that in the areas of epidemiologically not involved with human illness, many ticks will contain nonpathogenic rickettsiae. In the areas with a serious rickettsiosis problem there will be mostly pathogenic rickettsiae, although in a smaller proportion of the ticks. Putative pathogenic and nonpathogenic rickettsiae will be evaluated in two endothelial-target animal models of pathogenicity. If strains meeting epidemiologically and experimentally defined criteria for pathogenicity and nonpathogenicity are identified in the first two years, we during the third year we will delve into two hypothetical mechanisms of pathogenicity: temperature-dependence of Rickettsia sibirica growth and expression of cytopathic effect and phospholipase A2-associated cell membrane injury. The foreign collaborator is among the world's foremost medical entomologists and has extensive experience in rickettsiology, a rare combination currently. The project offers an opportunity for the Principal Investigator, an experimental pathologist, to direct a part of his studies of rickettsiae toward investigation of their pathogenic mechanisms, in principle converging with his ongoing active study of rickettsial structural and molecular composition as it relates to immunity.